1
UNIVERSITÀ DI PISA
Dipartimento di Medicina Clinica e Sperimentale
Prospective naturalistic study on BD-I and BD-II
patients: are clinical characteristics or pharmacologic
treatments related to relapses?
Relatore:
Chiar.ma Prof.ssa Liliana Dell’Osso
Candidata:
Irene Pergentini
2
INDEX
1. Summary p.3
2. Introduction p.7
2.1 Long-term treatment of Bipolar Disorder
2.2 Recent findings on Lithium Salts
3. Aims of the study p.18
4. Materials and methods
4.1 Subjects p.19
4.2 Procedure p.19
4.3 Assessment tools p.21
4.4 Statistical analysis p.26
5. Results p.27
6. Discussion and Conclusions p.32
7. Tables and figures p.40
3
1. Summary
Bipolar disorder (BD) is a chronic mood disorder, despite modern pharmacological therapeutic strategies more than half of all bipolar patients relapse within 2 years, with over 90% of bipolar patients having experienced at least 1 additional affective episode during their lifetime (Perlis et al., 2006). Many studies corroborate the importance to investigate and treat predictors of recurrences in bipolar-II and bipolar-I patients such as substance abuse or dependence, the presence of anxiety symptoms or of a comorbid eating disorder and residual mood symptoms early in recovery whose presence appears to increase the risk for depressive recurrence (Perlis et al., 2006; Judd et al., 2002).
Significant predictors of relapses in BD patients, are also previous mixed episodes and studies showed for example that early BD mixed-states could be followed by particularly severe later morbidity (Berk, Dodd et al. 2005, Vieta 2005, Gonzalez-Pinto, Aldama et al. 2007).
Management of bipolar patients is often complicated because of the risk of serious recurrences and very low percentage of patients who remain in remission (bipolar I patients: 28% for 4 years and about 10% for 5 years) (Goodwin, Jamison, 2007; Keller et al., 1993, Tohen et al., 1990).
4
The main goal of maintenance treatment of bipolar disorder is stabilizing mood and reducing inter-episodic symptoms. Lithium salts are the gold standard for acute and long-term management of bipolar disorder because of its prophylactic and antisuicidal properties. The aim of our prospective naturalistic study was to investigate the presence of a relation among age of onset, polarity of onset, previous clinical course, comorbidity and high frequency of recurrences in a sample of 266 patients and examine the clinical characteristics and the course of illness of a subgroup of 234 BD-I or BD-II outpatients treated with lithium salts or anti-epileptics drugs or with a combination of both. We studied a possible relationship between the kind of stabilization utilized and the characteristics of illness. Patients have been followed for a period of at least 8 months at Section of Psychiatry, Department of Clinical and Experimental Medicine, University of Pisa and at the Istituto di
Psicopatologia in Rome. Patient enrollment criteria were age 18-65
years and meeting DSM IV criteria for BD-I or BD-II or Koukopoulos’s criteria for mixed attenuated episodes. We used the SCID-I / P, SIMD and the LIFE scale to evaluate the diagnostic, clinical and therapeutic aspects. We divided the 234 patients into three groups according to the different treatments utilized for long term stabilization of Bipolar disorder: 51 patients with Lithium only, 56 patients stabilized with anticonvulsant drugs and 127 patients stabilized with a combination of
5
Lithium and anticonvulsant drugs. Our study highlights that Lithium and antiepileptic drugs combination was the most common treatment strategy used to stabilize patients in the sample.
From our findings, gender female, age, duration of follow-up, total mean number of previous episodes, frequency of past mixed episodes, resulted related to risk of recurrences..
Furthermore, patients taking lithium and anti-epileptics combination were more frequently affected by BD-I, had higher rates of mixed episodes in retrospective and prospective course, higher rates of lifetime psychotic symptoms, and showed higher rates of concomitant atypical antipsychotic prescription. Patients stabilized with anti-epileptics or lithium alone were more frequently BD-II, had higher rate of comorbidity and higher antidepressants concomitant prescription.
No significant difference emerged according to the duration of the follow up period among the three groups of treatment, so that we could suppose the long-term tolerance of lithium associated with anti-epileptic drugs was similar to the tolerability expected by using a single mood stabilizer. Overall, in our study, patients on a combination therapy, had evidenced the major improvement measured as the difference between the medium frequency of relapses in retrospective and prospective course, rather than the other patients treated on a single mood stabilizer.
6
Several limitations in the present study should be considered.
The most important are its small sample, the lack of randomization and the absence of a placebo group which not permitted to evaluate and draw conclusions about the efficacy of the treatments. Further investigations are required to confirm the present study's results.
7
2. Introduction
Bipolar disorder (BD) is a mood disorder characterized by recurrent manic, hypomanic, depressive and mixed episodes leading to substantial disability, cognitive impairment and mortality (Turvey, Coryell et al. 1999, Perugi, Micheli et al. 2000, Tohen, Strakowski et al. 2000, Tohen, Zarate et al. 2003, Paykel 2006, Huxley and Baldessarini 2007, Forty, Jones et al. 2009, Baldessarini, Bolzani et al. 2010).
Formal definitions of manic and depressive symptoms are included in the recently updated Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5; American Psychiatric Association, 2013) and such episodes are newly defined in DSM-5 as either a manic or hypomanic episode with mixed features or a depressive episode with mixed features, depending on which symptoms are predominant (American Psychiatric Association, 2013).
BD is a chronic disease which affects about 2,4% of the general population (Belmaker 2004, Merikangas, Jin et al. 2011) and increases to 6% for a broad range of bipolar spectrum disorders (Waraich et al., 2004). The economic burden of BD to society is enormous and the costs include the direct costs of treatment and indirect costs from reduced employment, productivity and functioning (Disalver, 2011). Several
8
studies investigating bipolar disorders have shown that polarity of onset can predict differences in symptomatology, course, and prognosis (Tundo et al., 2015) so that first episode polarity has been proposed as a marker to identify distinct subgroups of bipolar disorder (Goodwin and Jamison 2007, Baldessarini, Undurraga et al. 2012, Carvalho, McIntyre et al. 2014).
Particularly, a same-polarity-recurrence trend, reported in the literature, is especially strong in mixed-onset patients, both in BD I and in BD II (Tundo et al., 2015).
Because the first episode is often a depressive episode, an estimated 35– 45% of BD patients are misdiagnosed with unipolar depression, and delays of up to 20 years from the onset of symptoms to the first mood stabilizer treatment have been reported. (Goodwin et al.,2016; Merikangas et al., 2012). Particularly BD-II patients are less quickly identified and consequently receive over-prescription of concomitant antidepressants (Samalin et al., 2016).
These considerations highlight the need in routine clinical practice of better investigate the clinical characteristics associated with bipolar depression such as family history of BD, earlier onset of illness, seasonality, mood reactivity, switching on antidepressants and history of suicide attempt, to reach the correct diagnosis and proceed on effective treatments (Hirschfeld, 2014).
9
Moreover, people with BD experience prominent inter-episodic sub-syndromal mood symptoms, such as depressive residual symptoms, cognitive impairments or emotional dysregulation, which become chronic and are often a disabling feature in BD patients and an important component of the clinical picture (Judd et al., 2003, Samalin et al., 2016). The literature highlights that 30-60% of BD patients in clinical remission are living with significant functional impairment (MacQueen et al., 2001). Considering these evidences, it is reasonable hypothesize that persistent mood instability is a risk factor for clinically significant mood episodes and that a better mood stabilization improves outcomes (Saunders et al., 2016).
Despite modern pharmacological therapeutic strategies more than half of all bipolar patients relapse within 2 years, with over 90% of bipolar patients having experienced at least 1 additional affective episode during
their lifetime (Perlis et al., 2006).
In a recent study, Samhandl et al. (2014) found a statistical tendency indicating more relapses in bipolar II than bipolar I patients probably because their results showed that bipolar II patients suffered from more depressive episodes, had more psychiatric comorbidities, and received more antidepressants than the bipolar I group suggesting a role of these clinical characteristics in predicting relapses.
10
Other studies corroborate the importance to investigate and treat predictors of recurrences in bipolar-II and bipolar-I patients, such as the current substance abuse or dependence, the presence of anxiety symptoms and of a comorbid eating disorder whose presence appears to increase the risk for depressive recurrence (Perlis et al., 2006).
Residual mood symptoms early in recovery appear to be a powerful predictor of recurrence, particularly for depression; residual manic symptoms appear to confer risk for both manic and depressive recurrence (Judd et al., 2002). Poor sleep quality correlates with residual mood symptoms than could predicts mood episode recurrence (De Dios et al., 2012; Cretu et al., 2016),
Significant predictors of relapse in BD patients, are also previous mixed episodes and studies showed for example that early BD mixed-states could be followed by particularly severe later morbidity that includes a great deal of dysphoria, depression and suicide-risk; otherwise, their optimal treatment remains unclear and less studied than mania or bipolar depression (Berk, Dodd et al. 2005, Vieta 2005, Gonzalez-Pinto, Aldama et al. 2007). Poor adherence with pharmacological treatments by patients and stopping medications by psychiatrists or by patients themselves, are other two important factors to be considered related to high risk of relapses in BD because the consequent lack of prophylactic effect of
11
medications these behaviors act (Keller et al., 1992; Perlis et al., 2006; Samhalindl et al., 2014; Li et al., 2014).
Given that BD is an illness that is “biological in origin yet psychosocial in expression”, in a recent study conducted by Levenson et al., (2014), the impact of social rhythm disrupting (SRD) life events on bipolar relapse or recurrence has been examined. The effect of social rhythm instability due to life events seems to be the same whether the event has negative or positive valence and they act beginning a cascade of social and biological rhythm disruption that may lead to the onset of affective episodes in those vulnerable to bipolar disorder.
2.1 Long-term treatment of Bipolar Disorder
Management of bipolar patients is often complicated because of the risk of serious relapses and very low percentage of patients who remain in remission (bipolar I patients: 28% for 4 years and about 10% for 5 years) (Goodwin, Jamison, 2007; Keller et al., 1993, Tohen et al., 1990). The goal of maintenance treatment is to reach optimum or premorbid functioning which includes maintaining mood stability and a reduction in inter-episode symptoms (Miklowitz et al., 2014).
12
1960s and it has been the standard long-term therapy in Bipolar disorder for 40 years (Muzina and Calabrese, 2005) and remains the gold standard for acute and long-term management of bipolar disorder because of its prophylactic (in particular lithium has efficacy in preventing recurrence of manic episodes) and antisuicidal properties (Malhi et al., 2012). The lifetime suicide rates in BD is estimated to be 15% and if untreated, 1% of BD patients die by suicide annually another 4% attempt suicide (Jamison et al, 1986; Baldessarini et al., 2006a, Cramp et al.,2013).
Recent meta-analysis have highlighted the superiority of Lithium for maintenance of bipolar disorder (Miura et al., 2014), and a recent naturalistic study showed lower relapse rates in patients treated on Lithium than patients treated on other prophylactic agents (Shimandl et al., 2014).
In the literature, many clinical characteristics have previously been associated with a poor long-term treatment outcome during lithium regimen, what have been characterized as a poor prognosis factors (PPFs) (Perlis et al., 2004, Post et al., 2011, Post et al., 2010, Ketter et al., 2010, Post et al., 2016). The PPFs include the presence of a precedent history of rapid cycling, a comorbid anxiety disorder, early onset of bipolar illness, physical or sexual abuse. Overall, the first step in
13
BD patients with comorbidities especially anxiety disorders, is to reach mood stabilization, than consider specific treatment for anxiety management. Valproate has demonstrated effectiveness to be recommended as maintenance treatment in BD patients with anxiety disorders. (Mhali et al., 2015) but resulted less effective in the presence of greater number of prior episodes and carbamazepine was used more in the presence of rapid cycling and resulted one of the few drugs equally effective in patients with or without this clinical characteristic (Post et al., 2016).
Peselow and colleagues (2016), in their study comparing lithium, valproic acid and carbamazepine monotherapy on the prophylactic efficacy in the maintenance phase of bipolar disorder, found that Lithium resulted leading to a significantly fewer relapses in BD than antiepileptic drugs. These date were confirmed by a recent prospective naturalistic study by Samhandl and collegues (2014) who corroborated Lithium to be the most powerful prophylactic agent in the prevention of affective episodes in bipolar disorder, despite the emergence of various treatment alternatives in the last 2 decades, such as anticonvulsants and atypical antipsychotics.
Despite these evidences, BD seems difficult to maintain on monotherapy, with almost two-thirds of patients experiencing inadequate
14
response to lithium monotherapy and more requiring additional mood stabilizers (Calabrese et al., 2005).
Findings from a number clinical trials support the use of a combination therapy, particularly lithium and anticonvulsant drugs, such as Valproate, which have demonstrated effectiveness in combination and there is no indication that their pharmacodynamics interactions are contradictory (Miura et al., 2014). Both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy; this benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. (Balance, 2010). Similarly the combination of Lithium or Valproate plus antipsychotic drug seems to be more effective than monotherapy with a mood stabiliser in preventing manic episodes (Lin et al., 2006). The relation between patients’ polarity and drugs’ characteristics should be more clearly recognized and researched in future trials.
Potential limitations to long-term treatment effectiveness include the natural history of recurrent or chronic disorders, treatments of imperfect effectiveness, and the major challenge of nonadherence to long-term treatment (Baldessarini, 2013; Lingam and Scott, 2002; Pompili et al., 2013; Forte et al., 2015).
15
2.2 Recent findings on Lithium salts
There is now evidence that BD is related to progressive impairment in neurocognitive functioning, as well as to regional impairments in neuroplasticity, cellular resilience and adult neurogenesis (Chiu et al., 2013)
Several neuroimaging studies in BD patients have shown lithium treatment to increase cortical gray matter volumes, especially in the anterior cingulate and in the paralimbic cortices that are implicated in attention, motivation and emotional modulation, as well as the hippocampus volume (Machado-Vieira et al., 2009, Zarate et al.,2006).
Since the neuroprotective effects of lithium on brain structures have been shown even in healthy subjects and appear independent of prophylactic treatment response, Hajek and Weiner (2016) have recently hypothesized that lithium treatment might help maintain brain health even in patients without BD as well as could possibly demonstrate disease-modifying properties in neurodegenerative disorders.
The risk for cognitive impairment and dementia has been reported to be higher in patients with BD than in the general population, correlating with the duration of illness, as well as with the number of illness
16
episodes, especially the depressive ones, and the degree of impairment (Pfennig et al., 2014, Wingo et al., 2009).
Both preclinical and clinical studies have produced new evidence of lithium benefits in terms of preventing dementia through its action on GSK-3 (Young, 2011), leading to its investigation also in neurodegenerative disorders.
Lithium inhibition of the GSK-3 has also been hypothesized to produce neuroprotective effects in other neurodegenerative disease models, such as Parkinson Disease, tauopathies, Huntington’s Disease, Amyotrophic Lateral Sclerosis and Multiple sclerosis (Chiu et al., 2013, Wada et al., 2005, Forlenza et al., 2014) but more evidences need to be corroborated. Lithium potential neuroprotective functions have been also explored in neurodevelopmental disorders.
Mood disorders are also common in Autism Spectrum Disorders (ASDs) and should be systematically investigated in this population of children and adolescents. Approximately 50% of children and adolescents with ASD receive medication for comorbid behavioral/ADHD and mood symptoms, particularly stimulants, anti-epileptics and antipsychotics.
Despite lithium's established efficacy in controlling mood disorder symptoms in the neurotypical population, it has been rarely studied in children with ASD. Recent literature has showed it could be a different
17
option for children and adolescents with ASD who present with symptoms of a mood disorder, such as elevated moods/euphoria, mania, and paranoia, whether accompanied or not by irritability and sleep disturbances (Canitano, 2015; Siegel et al., 2014; Serret et al., 2015).
18
3. Aims of the study
The aim of the study was to examine the clinical characteristics and prospective course, in a sample of outpatients with either BD-I or BD-II, followed for a period of at least 8 months and naturalistically treated on mood stabilizers (lithium salts or anti-epileptics drugs, particularly valproic acid or carbamazepine) or with a combination of both. In this way the presence of clinical characteristics or treatment strategy, that could predict recurrences, was assessed.
Based on the currently available findings, we hypothesized that:
• Age of onset, polarity of onset, previous clinical course, comorbidity, could predict recurrences.
• Patients treated on lithium salts have different clinical characteristics than patients treated on anti-epileptics drugs, or on a combination of both.
• The mood stabilizers used would predict future Illness course characteristics, in terms of relapses (mixed or manic/hypomanic or depressive episodes).
19
4. Materials and methods 4.1 Subjects
In a sample of four hundred and seven bipolar patients recruited during a period of 4 years at the Section of Psychiatry, Department of Clinical and Experimental Medicine, University of Pisa, Italy and at the Istituto
di Psicopatologia in Rome, Italy (Tundo et al., 2015), a subgroup of two
hundred and sixty-six patients was screened for eligibility and longitudinally followed up for a period of at least 8 months.
Patient enrollment criteria were age 18-65 years and meeting DSM IV criteria for type I or II bipolar disorder (APA, 1994). Exclusion criteria were the presence of medical or neurological conditions inducing mood disorders.
4.2 Procedure
The study's two senior psychiatrists (LM, AT) used the Structured Clinical Interview for DSM IV Axis I Disorders-Patient Version (SCID-I/P) (First, R.L. et al. 1997) to interview all participants.
The Semi-structured Interview for Mood Disorder (Cassano, Musetti et al. 1987) was used to collect the participants' demographic and retrospective clinical data.
20
Diagnosis of manic, hypomanic, and depressive episode in BD-I and II, and of mixed episode in BD-I, was formulated according to DSM-IV criteria (APA, 1994). As there were no official criteria for diagnosing mixed episodes in BD-II we adopted Koukopoulos’s criteria (Koukopoulos, 1999), which have been validated by (Benazzi, Koukopoulos et al. 2004) and by (Sani, Vohringer et al. 2014).
LIFE (Longitudinal follow-up evaluation) (Keller, Lavori et al. 1987) was administered every 16 weeks in order to collect date on the prospective course of the disorder (in terms of number and polarity of recurrences) and on treatments.
Even in this case the diagnosis of manic, hypomanic, depressive and full blown mixed episode, was formulated according to DSM-IV criteria (APA, 1994) while the diagnosis of mixed attenuated episodes was assessed by Koukopoulos’s criteria (Koukopoulos 1999), cited above. For the purpose of this study, we divided patients into two groups, those with no relapses and those with one or more relapses during the follow up period.
Next, patients on mood stabilizers therapy have been separated into three groups according to the different type of stabilization used in the treatment of Bipolar disorder: patients with Lithium only (Li), patients stabilized with anticonvulsant drugs (Anti-epi, Valproate/
21
Carbamazepine), and patients stabilized on a combination of Lithium and anticonvulsant drugs (Li+Anti-epi).
All patients gave written informed consent for data collection and for their use in anonymous and aggregate form, and the local ethical committees approved the research project.
4.3 Assessment Tools
The diagnostic and symptomatology assessments were performed with the following tools:
• Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Version SCID-I / P (First, R.L. et al. 1997):
This interview is used for the diagnosis of most Axis I disorders according to the DSM IV criteria.
The SCID I for Axis I diagnosis consists of eight modules containing each questions to investigate the presence of symptoms-criteria for different diagnostic categories.
Each module is independent and can be used separately from the other according to specific searches.
The SCID I must be used by interviewers with good clinical experience and who have undergone adequate training.
22
The interview is organized according to the diagnostic categories of DSM-IV: the sequence of questions follows the structure of this manual and the different items explore the diagnostic criteria.
For this study the form relating to Mood Disorders was mainly used in order to adequately recruit patients with DB-I and DB-II and properly diagnose the different onset illness episode (depressive, hypo/manic, mixed), the previous illness episodes and the polarity of illness relapses too.
• Semi-structured Interview for Mood Disorders (SIMD) (Cassano, Musetti et al. 1987):
The SIMD-R is a semi-structured diagnostic interview for assessment of mood disorders.
It systematically collects information on different familiar, demographics, medical history and clinical aspects.
This interview has been developed to gather systematic information on family history, previous episode number and polarity, suicide attempts (current and lifetime), and psychotic symptoms of any polarity.
Thanks to this tool it was also possible checking the main affective diagnosis and the type of mood episode currently in progress.
Whenever possible, collateral clinical data, including information obtained from other informants as well as any available past medical records, were used to support patient information, and in particular, to
23
corroborate the onset age and polarity of the participants' first illness episode.
• Koukopoulos’s criteria for mixed depression (Koukopoulos 1999): These criteria are designed by Koukopoulos and validated by Benazzi et al. (2004) and by Sani et al. (2014).
In our study these criteria were used for defining mixed episode in patients with DB-II; particularly mixed episode in BD-II (or mixed depression) was defined as a major depressive episode plus three or more of the following eight symptoms: inner tension/agitation, racing or crowded thoughts, irritability or unprovoked feeling of rage, absence of signs of retardation, talkativeness, dramatic description of suffering or frequent spells of weeping, mood lability or marked reactivity, early insomnia.
Benazzi et al. (2004) and Sani et al. (2014) validated the Koukopoulos and Koukopoulos’s definition of agitated depression as a mixed state showing that it was associated with variables, which typically distinguished bipolar disorders from unipolar major depressive disorders, including bipolar family history.
Different combinations of the symptoms suggested in the diagnostic criteria of mixed depression, tested with multivariate regression, were significantly and strongly associated with bipolar predictor variables,
24
further supporting Kraepelin’s historical reassignment of agitated depression as mixed state.
Benazzi et al. (2004) even showed a very high frequency of mixed (agitated) depression in a sample of BP-II and unipolar outpatients (38.6%), supporting the clinical importance of mixed depression in outpatient clinical practice and the possible influence in the choice of pharmacological treatment for this particular subset of patients.
For these reasons, we decided to use these criteria to adequately identify patients with mixed features in our BD-II patients.
In our study, Koukoupoulos’criteria defined mixed episode in BD-II both for what concerned the polarity of onset, the previous illness episodes and the polarity of relapses in the follow-up.
• LIFE (Longitudinal Internal Follow-up Evaluation) (Keller, Lavori et al. 1987):
LIFE scale is a semi-structured interview used for the assessment of illness course of psychiatric disorders.
It allows you to record, in sufficient detail, the new episodes of illness and periods of remission during the follow-up, according to the criteria of the DSM IV (APA, 1994).
The National Institute of Mental Health-Clinical Research Branch Program on the Psychobiology of Depression from 1979 first used this tool, and it was originally drafted to evaluate the course of affective
25
disorders during a period of six months, but can be used to any psychiatric disorder and adapted to any length of time.
This scale also provided for the registration of changes in psychosocial functioning and in the pharmacological treatment, allowing a correlation with changes in psychopathology of the subject.
The patient is usually the first source of information but the interviewer can also make use of information obtained from medical records and patient's family and friends.
The scale consisted of six sections: psychopathology, not psychiatric disorders, psychiatric treatment, psychosocial adaptation scale, narrative report, and is usually administered every 16 weeks.
For our study sections 'psychopathology' and 'psychiatric treatment' have been used in the period of follow-up: the first is evaluated through a longitudinal survey system that takes into account the latest 16 weeks prior to the visit and provides, for each week, the presence and the quantification of the severity of symptoms for each disorder in question. Raters assigned, for each completed week of follow-up, a score quantifying the symptoms for each disorder that were present in that given week. Scores ranged from 1 (asymptomatic, returned to usual self) to 6 (definite criteria, very severe symptoms). For the purpose of this report, rates of scores for the three affective states, depression, mania,
26
and mixed states, were calculated over the period of prospective observation and were mutually exclusive.
The diagnosis of manic, hypomanic, and depressive relapse episodes in BD-I and II, and of mixed episode in BD-I, was formulated according to DSM-IV criteria (APA, 1994) while the diagnosis of mixed relapse episodes in BD-II was assessed by Koukopoulos’s criteria (Koukopoulos 1999), cited above.
A portion of the scale provides also for the registration of self-injury acts and suicide attempts, which are assessed according to a criterion of 'adequacy’, with a 7-point scale (0-6) and of ‘gravity’ with an 8-point scale (0-7).
In the section 'psychiatric treatment’, every week the treatment regimen adopted is recorded (hospitalization, day hospital, outpatient treatment). The type and dosage of all medications assumed by the patient, the number of applications of electroconvulsive therapy, duration, mode and the type of treatment sessions could be recorded too (for our study only the pharmacological component was considered).
4.4 Statistical analyses
Statistical analyses were conducted using IBM SPSS Statistics Version 21. Chi-square test or two-tailed Fisher’s exact test was used, as appropriate, to compare categorical variables.
27
One-way ANOVA followed by post-hoc Bonferroni’s test was utilized to compare parametric variables.
Kruskal-Wallis followed by Dunn’s test were used in case of three or more non-parametric variables and Mann-Whitney test in case of two non-parametric variables. To compare pair of date of non-parametric variables, Wilcoxon test was utilized.
Finally, Multiple Linear Regression Model was performed in order to estabilish predictors of higher frequency of relapses.
5. Results
The study included 266 patients, 57.5% with BP-I. During the follow-up (mean lenght 46.0 + 27.5 months) 35.7% had no relapses, 33.8% had 1 or 2 relapses, and 30.4% had > 3 relapses.
We compared demographic and clinical characteristics of patients with and without at least one relapse. Results are showed in Table 1 and in Table 2.
As far as baseline and past features are concerned, patients in the two groups did not differ in mean age, mean age of onset, and previous duration of illness. Number of previous episodes was higher in patients with at least one relapse (p .019), mainly due to the higher number of depressive episodes in this group (p .002). The length of follow-up was longer in patients with relapses, too (p .000) (see Table 1).
28
Comparisons between patients with and without relapses showed no differences in gender distribution, presence and type of comorbidity, polarity of onset, history of substance abuse, diagnosis distribution (bipolar I vs. bipolar II disorder), psychotic symptoms during one or more illness episodes (see Table 2).
In order to analyse the impact of several variables on the vulnerability to relapses, we conducted a linear multiple regression model. The multiple linear regression model provided the frequency of episodes (n per year) in the follow up period as dependent variable and a series of independent demographic and clinical variables (see Table 3). It showed that female gender, higher mean age and higher frequency of mixed past episodes were associated to higher frequency of relapses during follow up. Diagnosis of BD-I or BD-II, comorbidity, polarity of onset, substance use disorder and treatment with antidepressants, didn’t result related to higher risk of recurrences.
With the aim to evaluate possible relationship between treatment strategy and clinical characteristics in our naturalistic study, in the total sample we considered a subgroup of patients stabilized on Lithium or Anti-epileptics (Valproate or Carbamazepine) or on a combination of both. They were two hundred and thirty-four and BD-I patients were 142 (60.7%), patients were mostly female (n=141, 60.2%), unmarried (n= 132, 56.4%), and regularly employed (n= 165, 70.5%).
29
Lithium and antiepileptic drugs combination was the most common treatment strategy used to stabilize patients in the sample (n=127, 54.3%), followed by the use of Anti-epileptics alone (n=56, 23.9%) and Lithium alone (n=51, 21.8%).
No gender or marital or employment status differences emerged between the three groups of treatment (Table 4).
The medium age of patients and the age of onset of BD seem to be higher in the group treated on lithium and antiepileptics combination therapy than in the other two groups, with not significant difference. Furthermore, the total number of previous episodes and the number of previous depressive, manic/hypomanic or mixed episodes, are not significantly different among the three groups, even though appear higher in patients on lithium and antiepileptics combination therapy. The frequency of episodes per year in restrospecitve course and the length of illness didn’t significantly differ among the three groups (Table 5).
As shown in Table 6, patients treated on a combination of Lithium and Anti-epileptics drugs were more frequently with BD-I (p=.001) as compared with those treated on Lithium or Anti-epileptics, who were more frequently affected by BD-II (p=.001). Group of patients stabilized with anti-epileptics only had significant higher rates of comorbidity as
30
compared to the other two groups (p=.008), nevertheless there were no significant differences about the prevalence rate for the specific anxiety comorbidities and for substances use and polarity onset, among the three groups.
Patients on Anti-epileptics plus Lithium had higher rates of lifetime psychotic symptoms (p=.013) and showed higher rates of atypical antipsychotic concomitant prescriptions than the subgroup treated on anti-epileptics (p=.037) and lower rates of concomitant Antidepressants use than patients in the other two groups did (p=.002).
The mean number of episodes of any polarity in prospective course and the duration of follow up didn’t differ among three groups.
Always considering prospective course, the mean number of mixed episodes resulted significantly higher in patients on lithium and anti-epileptics combination than in other two groups of treatment (p=.007) while mean number of manic/hypomanic and depressive episodes didn’t significantly differ among three groups (Table 7).
The frequency of recurrences (mean number of episodes/ year) in the prospective course didn’t show any significant difference in the three groups of treatment.
The frequency of recurrences significantly decrease in prospective course in each group of treatment (Figure 1).
31
With the Mann-whitney test we put in evidence that patients stabilized on lithium plus antiepileptics showed decrease of the frequency of episodes greater than those on antiepileptics or lithium alone with a significant difference vs the group treated on antiepileptics (p=.035 (Figure 2).
32
6. Discussion and conclusions
Our study put in evidence remarkable findings, such as high relapse rate of affective episode: 64.2% of Bipolar I and Bipolar II patients had at least one relapse whithin follow up period. Other studies support these results, for example Silverstone and collegues (1998) found similar relapse rate in their naturalistic follow-up study on bipolar patients and more recently Simhandl et al. (2014) presented, in their 300 bipolar patients, relapse rate of 68%, in a 4-years follow-up period. Lower ralapse rate was described in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial, 1,469 bipolar patients were followed up during 24 months, with 48.5% experiencing recurrences (Perlis et al., 2006) and more recently in a Spanish naturalistic study where 12% of bipolar patients presented at least one relapse during a period of one-year follow-up (Montoya et al., 2010). These data might simply be explained by the shorter observation period (1-2 years) than our follow-up period that was 46.0 + 27.5 months. The lenght of the follow-up, in our findings, was significantly related to risk of recurrences and the number of previous illness episodes too, mainly due to the higher number of depressive episodes, according to results from the Zurich Cohort Study in which the risk of subsequent recurrences increases with the period of observation and with the number of previous episodes (Kessing et al., 2004; De Dios et al., 2012).
33
Also Perlis et al. (2006) corroborated our data showing a significant association between the number of previous affective episodes, in particular depressive episodes, and the high risk of relapses; Simhaland et al., (2014) didn’t confirm these results in their bipolar sample.
Furthermore, through a model regression, we showed that female gender, higher age and higher frequency of mixed past episodes were associated to higher frequency of recurrences during follow up. Mixed episodes are recognized to be a risk factor for relapses during the course of illness (Berk, Dodd et al. 2005, Vieta 2005, Gonzalez-Pinto, Aldama et al. 2007). For this reason, a correct diagnosis of mixed episodes in bipolar disorder becomes essential, in particular recognition of less severe mixed forms, in large part characterized by inner tension, mood lability, irritability, crow of thoughts, absence of retardation, that are not diagnosed with DSM-V TR criteria for mixed episodes and even not with DSM-5 criterion that exclude “overlapping” symptoms from the mixed features. We know mixed states are frequent, and validly diagnosing and treating them is central to the practice of psychiatry (Koukoupolos et al., 2009).
Interesting, in our naturalistic study, BD-I or BD-II diagnoses didn’t result related to higher risk of recurrences. On the contrary, Simhandl and collegues (2014) observed a tendency of bipolar II patients to have higher rates of recurrences probably because of the clinical
34
characteristics of bipolar II patients who suffered more psychiatric comorbidities and received more antidepressants than the bipolar I patients, suggesting a role of these clinical characteristics in predicting relapses.
Our analyses couldn’t confirm this hypothesis; the clinical features of our bipolar sample such as psychiatric anxiety comorbidity, substance use disorder and concomitant treatment with antidepressants, didn’t result related to higher risk of recurrences. Of note, in our sample concomitant prescription of antidepressants resulted higher in patients with no relapses, probably because the patients treated on higher rate of antidepressant medications represented a subgroup affected by less severe illness state, where the antidepressants given with caution by physicians, less probably determined manic/hypomanic switch or mixed states or emotional instability, all related to greater risk of recurrences (Judd et al., 2003, De Dios et al., 2012; Samalin et al., 2016).
About the presence of comorbidity, in contrast with our results, Simon et al. (2004) and Perlis et al. ( 2006), found poor outcome for individuals with anxiety comorbidity, in particular the letter demonstrated that among participants with anxiety disorders the rate of relapses during the observation period was higher, while they didn’t find any association between lifetime substance use disorder and recurrences but only a modest association with current substance abuse or dependence,
35
consistent with our findings. Yen and collegues (2016), on the other hand, found that anxiety comorbidity and substance use disorder, predicted less time to next affective episode. Polarity of onset, in our bipolar patients, wasn’t associated to relapses as in others naturalistic studies (Perlis et al., 2006; Li et al., 2014, Simhandl et al., 2014).
Findings of this naturalistic study showed that therapeutic strategy based on a combination of lithium and antiepileptic drugs is the most frequent in our sample of bipolar outpatients recruited in two Italian centers specialized in mood and anxiety disorders. Kessing et al. (2016), describing prescription patterns and changes in these patterns during last decade, for patients diagnosed with bipolar disorder in Denmark, found that lithium prescription drastically decreased and anti-epileptics prescription increased, in disagreement with the strong evidence for the maintenance effect of lithium as confirmed in a recent meta-analysis (Severus et al., 2014). From our findings, patients taking lithium and anti-epileptics were more frequently affected by BD-I, had higher rates of mixed episodes in retrospective and prospective course, higher rates of lifetime psychotic symptoms, and showed higher rates of concomitant atypical antipsychotic prescription than subgroup of patients stabilized with anti-epileptics alone but not than those on lithium alone and they had lower concomitant antidepressant prescription than patients
36
stabilized with anti-epileptics or lithium monotherapy. The subgroup treated on a combination therapy seemed to be affected by a more severe disease state, because of the clinical characteristics described that have previously been associated with a poor long-term treatment outcome (Post et al., 2011). According to guidelines for maintenance treatment of bipolar disorder (APA, 2013; National Institute for Health and care Excellence (NICE), 2014), in this group of patients concomitant antidepressant prescription was lower than in other two groups because of the risk of switch to mania or mood instability while concomitant antipsychotics prescription was higher because the supposed greater severity of illness in this group of patients required augmentation therapy to reach stabilization and to treat psychotic symptoms (Goodwin at al., 2016).
In our sample bipolar II patients were more frequently stabilized on anti-epileptics alone than on lithium or on a combination of both according to the literature in which we found bipolar II patients receiving anticonvulsants more frequently than bipolar I patients (Simhandl et al., 2014). Probably, comorbidity prevalent in this sub-group of patients could explain these findings.
Data presented by Malhi and colleagues’ (2015), who evidenced that the use of anti-epileptics alone is the most common therapeutic choice
37
utilized in patients with anxious comorbidities, corroborated our results while Peselow et al. (2016) supported lithium as the most effective drug independent of comorbidities. In our study, the presence of multiple anxiety comorbidities also could clarify the higher antidepressants concomitant prescription in these patients than in patients on combination therapy.
In our data, no significant difference emerged according to the duration of the follow up period among the three groups of treatment so that we could suppose the long-term tolerance of lithium associated with anti-epileptic drugs was similar to the tolerability expected by using a single mood stabilizer. In contrast to our findings, Peselow et al., (2015), in a recent study, comparing valproate, carbamazepine and lithium, found out that lithium was better tolerated than anti-epileptics, while Bowden et al. (2000) observed in their studies the superiority of valproate over lithium on the basis of higher level of early drop-out because of intolerance of lithium. Cipriani and colleagues (2013) corroborated date about the difference between the combination of lithium and valproate and valproate or lithium alone in terms of tolerability, in favour of monotherapy.
Overall, in our study, the three groups of treatment didn’t show significant difference in term of frequency of recurrences in the period
38
before the entry to study and in prospective course but each group had evidenced improvement measured as the difference between the medium frequency of relapses in retrospective and prospective course. Patients on a combination therapy, had evidenced the major improvement than the other patients treated on a single mood stabilizer, particularly anti-epileptics. About this, many trials support the use of combination medications, in particular lithium and valproate which have demonstrated major effectiveness in combination on maintenance of bipolar disorder (Solomon et al., 1998, BALANCE investigators and collaborators, 2010).
In light of these evidences, the outcome of bipolar patients is not optimistic, because of high recurrence rates, high non-compliance rates and low recovery rates. Clinical experts should pay more attention to the situation individualizing possible predictors of recurrences and the best maintenance drug treatment for each patient, in accordance with the efficacy and tolerability of long-term treatments of documented efficacy. Several limitations in the present study should be considered.
The most important are its small sample, the lack of randomization and the absence of a placebo group which not permitted to evaluate and draw conclusions about the efficacy of the treatments. In addition, variations in doses of medications received by study participants and plasma levels concentrations have not been controlled in this analysis. Anyway, in our
39
naturalistic study we were underlining the prescriptions patterns of mood stabilizers drugs in a sample of BD-I and BD-II outpatients and describing the characteristics of illness in each group of treatment.
40
7. Tables and figures
Table 1: Clinical and demographic features in patients with and without relapses Variables Patients with relapses mean±SD (171) Patients without relapses mean±SD (95) p Age 40.23±13.39 35.56±11.97 0.218 Age of onset 28.10±11.54 26.15±10.29 0.194 Previous illness duration (months) 141.97±118.98 125.31±111.99 0.151 N. previous manic/hypomanic episodes 7.30±15.58 4.46±7.32 0.379 N. previous depressive episodes 7.79±11.73 4.01±5.69 0.002 N. previous mixed episodes 3.10±13.20 0.95±1.81 0.660 N. total previous episodes 16.74±31.25 9.05±11.72 0.019 Duration of follow-up (months) 49.92±25.91 39.15±29.31 0.000
41
Table 2: Clinical and demographic features in patients with and without relapses Variables Patienst with relapses (N=171) Patients without relapses (N=95) p N (%) N (%) Gender Male 57 (33.3) 43 (45.3) 0.073 Female 114 (66.7) 52 (54.7) Comorbidity 106 (62.0) 57 (60.0) 0.851 Type of comorbidity Panic disorder 26 (15.2) 13 (13.7) 0.606 Obsessive-Compulsive Disorder 22 (12.9) 14 (14.7) Social Anxiety disorder 3 (1.8) 2 (2.1) Eating Disorders 1 (0.6) 3 (3.2) Multiple comorbidity 54 (31.6) 25 (26.3) Diagnosis DB-I 97 (56.7) 56 (58.9) 0.824 DB-II 74 (43.3) 39 (41.1) Substance abuse 17 (9.9) 12 (12.6) 0.639 Polarity of onset Depressive onset 111 (64.9) 59 (62.1) 0.482 Manic/hypomanic onset 28 (16.4) 21 (22.1) Mixed onset 32 (18.7) 15 (15.8) Delusions 73 (44.0) 36 (40.4) 0.682 Antidepressants 50 (52.0) 110 (64.0) 0.062
42
Table 3: Multiple Linear Regression Model
Model Unstandardiz ed Coefficients B (SE) IC 95% p Lower bound Upper bound Constant .129 (.252) Gender (female) -.267 (.102) -.469 -.065 .010 age .013 (.004) .005 .022 .002
Diagnosis (Bipolar I vs. Bipolar II) -.125 (.117) -.355 .105 .285
Comorbidity .035 (.101) -.164 .234 .729
Hypo/manic polarity of onset .174 (.164) -.150 .498 .292 Depressive polarity of onset -.009 (.139) -.282 .265 .949 Previous hypo/manic episodes (Number per
year)
-.068 (.056) -.178 .043 .230 Previous depressive episodes (Number per year) .076 (.052) -.027 .179 .145 Previous mixed episodes (Number per year) .285 (.070) .148 .423 .000 Treatment with antidepressants -.004 (.105) -.212 .204 .968 Substance use disorder .005 (.150) -.292 .302 .974
43
Table 4: Demographic features in patients treated on mood stabilizers Antiepi (n=56) n (%) Li (n=51) n(%) Li+Antiepi (n=127) n (%) X2 p Males (n=93) Females (n=141) 22 (39.3%) 34 (60.7%) 14 (27.5%) 37 (72.5%) 57 (44.9%) 70 (55.1%) 4.623 0.099 Married (n=102) Single (n=132) 22 (39.3%) 34 (60.7%) 22 (43.1%) 29 (56.9%) 58 (45.7%) 69 (54.3%) 0.649 0.723 Employed (n=165) Unemployed (n=69) 34 (60.7%) 22 (39.3%) 35 (68.6%) 16 (31.4%) 96 (75.6%) 31 (24.4%) 4.248 0.120
44
Table 5: Demographic features and retrospective course
Antiepi (n=56) (Mean±SD) Li (n=51) (Mean±SD) Li+Antiepi (n=127) (Mean±SD) P Age 37.18±13.53 38.57±13.38 39.27±12.01 0.591 Age of onset 25.16±10.27 27.46±11.58 27.87±9.88 0.258 Length of illness (months) 144.14±144.46 135.88±89.73 134.15±117.41 0.634 N. total previous episodes 11.20±15.40 9.74±12.74 18.05±34.87 0.113 N. previous depressive episodes 5.62±7.88 5.29±6.98 7.44±12.54 0.369 N. previous manic episodes 5.85±9.09 3.82±6.18 8.06±17.19 0.217 N. previous mixed episodes 0.62±1.66 1.21±4.18 3.66±14.83 0.219 Retrospective total episodes/year 1.35±1.73 1.34±2.06 1.99±3.35 0.229
45
Table 6: Clinical features
Antiepi (n=56) n (%) Li (n=51) n (%) Li+Antiepi (n=127) n (%) χ 2 p Post-hoc analysis Sig p<.05 Bipolar I 24 (42.9) 27(52.9 91 (71.7) 15.14 0.001 Antiepi, Li < Li + Antiepi Bipolar II 32 (57.1) 24(47.1) 36 (28.3) Comorbidity 44 (78.6) 31 (60.8) 69 (54.3) 9.664 0.008 Antiepi > Li + Antiepi Comorbidity of Panic Disorder 12 (21.4) 9 (17.6) 16 (12.6) 2.441 0.295 Comorbidity of Obsessive-Compulsive Disorder 4 (7.1) 9 (17.6) 20 (15.7) 3.052 0.217 Comorbidity of Social Anxiety Disorder 1 (1.8) 0 (0) 3 (2.4) 1.211 0.546 Substance Abuse 5 (8.9) 2 (3.9) 18 (14.2) 4.245 0.120 Depressive Onset 41 (73.2) 35 (68.6) 71 (55.9) 6.175 0.186 Manic/Hypomanic Onset 9 (16.1) 8 (15.7) 30 (23.6) Mixed Onset 6 (10.7) 8 (15.7) 26 (20.5) Lifetime psychotic Symptoms (Delusion) 19 (34.5) 15 (31.9) 65 (52.8) 8.687 0.013 Antiepi, Li< Antiepi + Li Concomitant antidepressant drugs 42 (75.0) 33 (64.7) 62 (48.8) 11.99 0.002 Li+ Antiepi < Li, Antiepi Concomitant antipsychotic drugs 9 (16.1) 10 (19.6) 41 (68.3) 6.602 0.037 Antiepi < Li + Antiepi
46
Table 7: Prospective course
Antiepi (n=56) (Mean±SD) Li (n=51) (Mean±SD) Li+Antiepi (n=127) (Mean±SD) p Post-hoc analysis Sig p< .05 Duration of follow-up (months) 44.48±27.49 48.80±23.67 46.26±29.14 0.416 N. total episodes (any polarity) 1.95±2.47 1.73±2.18 2.09±2.39 0.640 N. depressive episodes 1.18±1.93 1.12±1.69 0.87±1.23 0.384 N. manic episodes 0.59±1.20 0.41±0.69 0.69±1.20 0.333 N. mixed episodes 0.18±0.47 0.20±0.49 0.54±1.04 0.007 Li, Antiepi < Li+ Antiepi Prospective total episodes/year 0.54±0.58 0.46±0.72 0.59±0.72 0.515
47 Figure 1 0 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 1,8 2 Antiepilectics drugs Lithium Antiepilectics drugs + Lithium 1,35 1,34 1,99 0,54 0,46 0,61
Frequency of recurrences in
retrospective and prospective course
Retrospective total episodes/ year Prospective total episodes/ year p=.004 p=.000 p=.00048 Figure 2 0 0,2 0,4 0,6 0,8 1 1,2 1,4 Antiepilectics
drugs Lithium Antiepilectics drugs + Lithium 0,81 0,88 1,38
Frequency reduction of recurrences
in three groups of treatment
Li + Antiepi vs Antiepi Z= 2.11 p= .035 Li + Antiepi vs Li Z=1.589 p= .11249
8. References
Akiskal HS. The bipolar spectrum: new concepts in classification and diagnosis. Psychiatry Update: The American Psychiatric Association
Annual Review 1983; 2.
American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders (4-th text revised ed.) Washington DC: American Psychiatric Association.
American Psychiatric Association, 2013. Diagnostic and Statistical Manual of Mental Disorders (5th Ed.). Washington DC: American Psychiatric Association.
Balance investigators and collaborators, Geddes JR, Goodwin GM, Rendell J, Azorin JM, Cipriani A, Ostacher MJ, Morriss R, Alder N, Juszczak E. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. TheLancet 2010; 375: 385-395.
Baldessarini R. J., Bolzani L., Cruz N., Jones P. B., Lai M., Lepri B., Perez J., Salvatore P., Tohen M., Tondo L. & Vieta E. Onset-Age Of
50
Bipolar Disorders At Six International Sites. The Journal of
Affective Disorders 2010; 121: 143-146.
Baldessarini R. J., Salvatore P., Khalsa H. M., Gebre-Medhin P., Imaz
H., Gonzalez-Pinto A., Perez J., Cruz N., Maggini C. & Tohen M. 2010b. Morbidity in 303 first-episodes bipolar I disorder patients. The
International Journal of Bipolar Disorders 2010; 12: 264-270.
Baldessarini R. J., Undurraga J., Vazquez G. H., Tondo L., Salvatore P., Ha K., Khalsa H. M., Lepri B., Ha T. H., Chang J. S., Tohen M. & Vieta E. 2012. Predominant Recurrence Polarity Among 928 Adult International Bipolar I Disorder Patients. Acta Psychiatrica Scandinavica 2012; 125: 293-302.
Baldessarini, R.J, Chemotherapy in Psychiatry. Springer, New York, NY. 2013.
Bauer M, Alda M, Priller J, Young LT; International Group For The Study Of Lithium Treated Patients (IGSLI). Implications of the
51
neuroprotective effects of lithium for the treatment of bipolar and neurodegenerative disorders. Pharmacopsychiatry 2003; 36: 250-254.
Berk M., Dodd S. & Berk L. The management of bipolar disorder in primary care: a review of existing and emerging therapies.
Psychiatry and Clinical Neuroscience 2005; 59: 229-239.
Calabrese JR, Suppes T, Bowden CL, et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 study group. The Journal of Clinical Psychiatry 2000; 61(11): 841-850.
Calabrese JR, Shelton MD., Rapport DJ. Et al. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. The American Journal of Psychiatry 2005; 162: 2152-2161.
Canitano R . Mood Stabilizers in Children and Adolescents With Autism
52
Carvalho A. F., Mcintyre R. S., Dimelis D., Gonda X., Berk M., Nunes-Neto P. R., Cha D. S., Hyphantis T. N., Angst J. & Fountoulakis K. N. Predominant polarity as a course specifier for bipolar disorder: a systematic review. Journal of Affective Disorders 2014; 163: 56-64.
Chen C., Lin S.. Carbamazepine treatment of bipolar disorder: a retrospective evaluation of naturalistic long-term outcomes. BMC
Psychiatry 2012; 12: 47.
Chiu CT, Wang Z, Hunsberger JG, Chuang DM. Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder.
Pharmacological Reviews 2013; 65(1): 105-142.
Cretu JB, Culver JL, Goffin KC2, Shah S, Ketter TA. Sleep, residual mood symptoms, and time to relapse in recovered patients with bipolar disorder. J Affect Disord. 2016 Jan 15;190:162-6.
De Dios C1, Ezquiaga E, Agud JL, Vieta E, Soler B, García-López A
53
cohort of bipolar disorder outpatients. J Affect Disord. 2012 Dec 20;143(1-3):160-5.
Denayer A, Van Esch H, de Ravel T, et al. Neuropsychopathology in 7 Patients with the 22q13 Deletion Syndrome: Presence of Bipolar Disorder and Progressive Loss of Skills. Molecular Syndromology 2012; 3(1): 14-20.
Dilsaver S. C. An estimate of the minimum economic burden of bipolar I and II disorders in the United States: 2009. Journal of Affective
Disorders 2011; 129: 79-83.
Duman RS. Depression: a case of neuronal life and death? Biological
Psychiatry 2004; 56(3) : 140-145.
Durand CM, Betancur C, Boeckers TM, et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genetics 2007; 39(1): 25-27.
54
Forlenza OV, De-Paula VJ, Diniz BS. Neuroprotective effects of lithium: implications for the treatment of Alzheimer's disease and related neurodegenerative disorders. ACS Chemical Neuroscience 2014; 5(6): 443-450.
Forte A, Baldessarini RJ, Tondo L, Vázquez GH, Pompili M, Girardi P
Long-term morbidity in bipolar-I, bipolar-II, and unipolar major depressive disorders. J Affect Disord. 2015 Jun 1;178:71-8. 2015 Mar 3.
Forty L., Jones L., Jones I., Smith D. J., Caesar S., Fraser C., Gordon-Smith K., Hyde S. & Craddock N. Polarity at illness onset in bipolar I disorder and clinical course of illness. The International Journal of
Bipolar Disorders 2009; 11: 82-88.
Gonzalez-Pinto A., Aldama A., Gonzalez C., Mosquera F., Arrasate M. & Vieta E. Predictors of suicide in first-episode affective and nonaffective psychotic inpatients: five-year follow-up of patients from a catchment area in Vitoria, Spain. Journal of Clinical Psychiatry 2007; 68: 242-247.
55
Goodwin GM, Haddad PM, Ferrier IN, Aronson JK, Barnes T, Cipriani A, Coghill DR, Fazel S, Geddes JR, Grunze H, Holmes EA, Howes O, Hudson S, Hunt N, Jones I, Macmillan IC, McAllister-Williams H, Miklowitz DR, Morriss R, Munafo M, Paton C, Saharkian BJ, Saunders K, Sinclair J, Taylor D, Vieta E, Young AH. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. Journal of
Psychopharmacology, 2016; 30: 495-553.
Goodwin FK, Jamison KR. Manic-depressive illness, 2nd edn. Oxford, UK: Oxford University Press, 2007.
Grunze H, Vieta E, Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders. Update 2012 on the long-term treatment of bipolar disorder. World Journal of Biological Psychiatry 2013; 14(3): 154-219.
Grunze HC. Anticonvulsants in bipolar disorder. Journal of Mental
Health 2010; 19(2): 127-141.
56
depressive disorder. J. A ect. Disord. 169, 12–16 (2014) .
Huxley, N. & Baldessarini, R. J. Disability and its treatment in bipolar disorder patients. The International Journal of Bipolar Disorders 2007; 9: 183-196.
Keller MB, Lavori PW, Kane JM, Gelenberg AJ, Rosenbaum JF, Walzer EA, Baker LA: Subsyndromal symptoms in bipolar disor- der: a
comparison of standard and low serum levels of lithium. Arch Gen
Psychiatry 1992; 49:371–376
Keller MB, Lavori PW, Coryell W, Endicott J, Mueller TI. Bipolar I: a five-year prospective follow-up. The Journal of Nervous and Mental
57
Kessing LV, Forman JL, Andersen PK. Does lithium protect against dementia? The International Journal of Bipolar Disorders 2010; 12(1): 87-94.
Kessing LV, Sondergard L, Forman JL, Andersen PK. Lithium treatment and risk of dementia. Archives of General Psychiatry 2008; 65(11): 1331-1335.
Kessing LV, Hansen MG, Andersen PK, et al. The predictive effect of episodes on the risk of recurrence in depressive and bipolar disorders: a life-long perspective. Acta Psychiatr Scand. 2004;109(5):339–344
Judd LL, Akiskal HS, Schettler PJ, Coryell W, Endicott J, Maser JD, Solomon DA, Leon AC, Keller MB: A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003; 60:261–269
Li C, Chen C, Qiu B, Yang G. A 2-year follow-up study of discharged
psychiatric patients with bipolar disorder. Psychiatry Res. 2014 Aug 15;218(1-2):75-8.
58
Lin D, Mok H, Yatham LN. Polytherapy in bipolar disorder. CNS Drugs.
2006;20(1):29-42.
Lingam, R., Scott, J, Treatment non-adherence in affective disorders. Acta
Psychiatr. Scand. 105, 164–172. 2002.
Machado-Vieira R, Manji HK, Zarate CA Jr. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. The International Journal of Bipolar
Disorders 2009; 11: 92-109.
Machado-Vieira R, Soeiro-De-Souza MG, Richards EM, Teixeira AL, Zarate CA Jr. Multiple levels of impaired neural plasticity and cellular resilience in bipolar disorder: developing treatments using an integrated
59
translational approach. The World Journal of Biological Psychiatry 2014; 15(2): 84-95.
MacQueen GM, Young LT, Joffe RT. A review of psychological outcome in patients with bipolar disorder. Acta Psychiatrica Scandinavica 2001; 103: 163-170.
Merikangas KR, Jin R, He JP, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Archives
of General Psychiatry 2011; 68: 241-51.
Mitchell P., Malhi G. The expanding pharmacopeia of bipolar disorder.
The Annual Review of Medicine 2002; 53: 173-178.
Montoya A, Tohen M, Vieta E, et al. Functioning and symptomatic outcomes in patients with bipolar I disorder in syndromal remission: a 1-year, prospective, observational cohort study. J Affect Disord. 2010; 127(1–3):50–57.doi:10.1016/j.j
60
Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer’s disease in elderly patients with bipolar disorder. The British Journal of
Psychiatry 2007; 190: 359-360.
Paykel, E. S. Depression: Major Problem For Public Health. Social
Psychiatry and Psychiatric Epidemiology 2006; 15: 4-10.
Perlis RH, Ostacher MJ, Patel JK, Marangell LB, Zhang H, Wisniewski SR,
Ketter TA, Miklowitz DJ, Otto MW, Gyulai L, Reilly-Harrington NA,
Nierenberg AA, Sachs GS, Thase ME. Predictors of recurrence in bipolar
disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006 Feb;163(2):217-24.
Perugi G., Micheli C., Akiskal H. S., Madaro D., Socci C., Quilici C. & Musetti L. Polarity of the first episode, clinical characteristics, and course of manic depressive illness: a systematic retrospective
61
investigation of 320 bipolar I patients. Comprehensive Psychiatry 2000; 41(1): 13-18.
Pfennig A, Alda M, Young T, et al. Prophylactic lithium treatment and cognitive performance in patients with a long history of bipolar illness: no simple answers in complex disease-treatment interplay.
The International Journal of Bipolar Disorders 2014; 2:1.
Pichler E. M., Hattwich G., Grunze H., Muehlbacher M. Safety and tolerability of anticonvulsant medication in bipolar disorder. Expert
Opinion on Drug Safety 2015; 14: 1703-1724.
Pompili, M., Venturini, P., Palermo, M., Stefani, H., Seretti, M.E., Lamis, D.A., Serafini, G., Amore, M., Girardi, P. Mood disorders medications: predictors of nonadherence: review of the current literature.
Expert Rev. Neurother. 13, 809–825, 2013.
Samalin L, Reinare M, De Chazeron I, et al. Course of residual symptoms according to the duration of euthymia in remitted bipolar patients. Acta Psychiatrica Scandinavica 2016; 1:8.
62
Samalin L, De Chazeron I, Vieta E, et al., Residual symptoms and specific functional impairments in euthymic patients with bipolar disorder. Bipolar disorders 2016; 18: 164-173.
Samalin L, Eduard V, Tarek A. O., Uddin MM. J., Abhari S. A., Nacef F, Mishyiev V, AizenbergD, Ratner Y, Melas-Melt L, Sedeki I and l Llorca P.M. Management of bipolar disorder in the intercontinental region: an international, multicenter, non- interventional, cross-sectional study in real-life conditions . Scientific Reposrt 2016
Serret S, Thümmler S, Dor E, Vesperini S, Santos A, Askenazy F. Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports. BMC
Psychiatry 2015; 15: 107.
Severus E, Taylor M J, Sauer C, Pfennig A, Ritter P, Bauer M, Geddes JR. Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. The International Journal of
